While passive delivery of drugs to metastatic tumors via the enhanced permeability and retention (EPR) effect has clear clinical significance, the selectivity for tumor versus normal tissue is unsatisfactory, particularly for gene therapies. Enabling image-guided drug delivery (IGDD) would be a valuable strategy to decrease off target effects. Here, we intend to leverage image-guided radiation (IGRT) as a means to target non-viral gene therapy vectors to tumors. Significantly, image-guided radiotherapy already has an established role in treating prostate cancer patients who have developed distant metastatic disease. Here, magnetic resonance (MR) and/or computed tomography (CT) imaging is used to allow precise aiming of radiation to the metastasis, allowing delivery of ablative doses to the tumor while inducing minimal damage to surrounding normal tissue. Importantly, the radiation doses used in IGRT not only kill cancer cells but also alter the tumor microenvironment, leading to increased permeability of tumor blood vessels. We have modeled IGRT of metastatic prostate cancer in mice using MR tumor imaging, image fusion with the on-board CT in the X-RAD 225Cx image-guided small animal radiation device, and treatment planning to deliver precision irradiation to the tumor. Our studies reveal increased vascular permeability in the irradiated tumors, and demonstrate both rapid accumulation and long-term retention of macromolecular imaging agents, an effect that we have named image-guided radiation-induced permeability (IGRIP). We have leveraged IGRIP to enable a novel approach to image-guided drug delivery by targeting nanoparticles to tumors. Here, we will further study and optimize IGRIP as a tool for IGDD and apply this approach to enable tumor-targeted delivery of gene therapy. We will develop a new class of non-viral vector nanoparticle nucleic acid carriers that remain stable in circulation and are delivered efficiently by IGRIP. As a model for translation, we will evaluate IGRIP for image-guided delivery of gene-directed enzyme-prodrug therapy and evaluate this as a strategy to potentiate the effects of radiation. Then, toward translation of personalized image-guided gene therapy, we will evaluate IGRIP as a tool to deliver RNAi for knock-downs and CRISPR nuclease for knock outs targeting oncogenes and DNA repair factors. We hope to enable a new approach wherein radiation is used to drive gene therapy into metastases as a route to improving treatment outcomes by achieving durable local and systemic control.